RESUMO
OBJECTIVES: This study aimed to determine the usefulness of electrophysiological exercise tests. The significance of slightly abnormal exercise tests was also examined. METHODS: We identified all the patients who had undergone exercise testing between February 2007 to June 2022 in Tampere University Hospital, Finland. Their medical records after diagnostic workup and exercise test reports were reviewed. A binary logistic regression was performed to evaluate the association between positive test result in short exercise test, long exercise test, or short exercise test with cooling and genetically confirmed skeletal muscle channelopathy or myotonic disorder. RESULTS: We identified 256 patients. 27 patients were diagnosed with nondystrophic myotonia, periodic paralysis, myotonic dystrophy type 1, myotonic dystrophy type 2, or other specified myopathy. 14 patients were suspected to have a skeletal muscle channelopathy, but pathogenic variants could not be identified. The remaining 215 patients were diagnosed with other conditions than skeletal muscle channelopathy or myotonic disorder. The combined sensitivity of exercise tests was 59.3% and specificity 99.1%. Abnormal exercise test result was associated with increased risk of skeletal muscle channelopathy or myotonic disorder (OR 164.3, 95% CI 28.3-954.6, p < 0.001). CONCLUSIONS: Electrophysiological exercise test is not optimal to exclude skeletal muscle channelopathy. It may be useful if a skeletal muscle channelopathy is suspected and genetic testing is negative or indeterminate and further evidence is required. Slightly abnormal exercise test results are possible in various conditions and result from different aetiologies. There is a demand for neurophysiological studies with higher sensitivity to detect skeletal muscle channelopathies.
Assuntos
Canalopatias , Transtornos Miotônicos , Distrofia Miotônica , Humanos , Teste de Esforço , Estudos Retrospectivos , Canalopatias/diagnóstico , Canalopatias/genética , Músculo Esquelético , Transtornos Miotônicos/diagnóstico , Transtornos Miotônicos/genéticaRESUMO
INTRODUCTION: Skeletal muscle channelopathies (SMCs) are a heterogenous group of disorders, caused by mutations in skeletal ion channels leading to abnormal muscle excitability, resulting in either delayed muscle relaxation (myotonia) which characterizes non-dystrophic myotonias (NDMs), or membrane transient inactivation, causing episodic weakness, typical of periodic paralyses (PPs). AREAS COVERED: SMCs include myotonia congenita, paramyotonia congenita, and sodium-channel myotonia among NDMs, and hyper-normokalemic, hypokalemic, or late-onset periodic paralyses among PPs. When suspecting an SMC, a structured diagnostic approach is required. Detailed personal and family history and clinical examination are essential, while neurophysiological tests should confirm myotonia and rule out alternative diagnosis. Moreover, specific electrodiagnostic studies are important to further define the phenotype of de novo cases and drive molecular analyses together with clinical data. Definite diagnosis is achieved through genetic testing, either with Sanger sequencing or multigene next-generation sequencing panel. In still unsolved patients, more advanced techniques, as exome-variant sequencing or whole-genome sequencing, may be considered in expert centers. EXPERT OPINION: The diagnostic approach to SMC is still mainly based on clinical data; moreover, definite diagnosis is sometimes complicated by the difficulty to establish a proper genotype-phenotype correlation. Lastly, further studies are needed to allow the genetic characterization of unsolved patients.
Assuntos
Canalopatias , Miotonia , Transtornos Miotônicos , Paralisias Periódicas Familiares , Humanos , Miotonia/diagnóstico , Miotonia/genética , Canalopatias/diagnóstico , Canalopatias/genética , Músculo Esquelético , Transtornos Miotônicos/genética , Mutação , ParalisiaRESUMO
Muscle channelopathies encompass a wide range of mainly episodic conditions that are characterized by muscle stiffness and weakness. The myotonic conditions, characterized predominantly by stiffness, include myotonia congenita, paramyotonia congenita, and sodium channel myotonia. The periodic paralysis conditions include hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and Andersen-Tawil syndrome. Clinical history is key, and diagnosis is confirmed by next-generation genetic sequencing of a panel of known genes but can also be supplemented by neurophysiology studies and MRI. As genetic testing expands, so have the spectrum of phenotypes seen including pediatric presentations and congenital myopathies. Management of these conditions requires a multidisciplinary approach with extra support needed when patients require anesthetics or when pregnant. Patients with Andersen-Tawil syndrome will also need cardiac input. Diagnosis is important as symptomatic treatment is available for all of these conditions but need to be tailored to the gene and variant of the patient.
Assuntos
Síndrome de Andersen , Canalopatias , Transtornos Miotônicos , Paralisia Periódica Hiperpotassêmica , Humanos , Síndrome de Andersen/genética , Canalopatias/genética , Paralisia Periódica Hiperpotassêmica/genética , Transtornos Miotônicos/diagnóstico , Transtornos Miotônicos/genética , Músculo Esquelético , Paralisia , MutaçãoRESUMO
We provide an up-to-date and accurate minimum point prevalence of genetically defined skeletal muscle channelopathies which is important for understanding the population impact, planning for treatment needs and future clinical trials. Skeletal muscle channelopathies include myotonia congenita (MC), sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (hyperPP), hypokalemic periodic paralysis (hypoPP) and Andersen- Tawil Syndrome (ATS). Patients referred to the UK national referral centre for skeletal muscle channelopathies and living in UK were included to calculate the minimum point prevalence using the latest data from the Office for National Statistics population estimate. We calculated a minimum point prevalence of all skeletal muscle channelopathies of 1.99/100 000 (95% CI 1.981-1.999). The minimum point prevalence of MC due to CLCN1 variants is 1.13/100 000 (95% CI 1.123-1.137), SCN4A variants which encode for PMC and SCM is 0.35/100 000 (95% CI 0.346 - 0.354) and for periodic paralysis (HyperPP and HypoPP) 0.41/100 000 (95% CI 0.406-0.414). The minimum point prevalence for ATS is 0.1/100 000 (95% CI 0.098-0.102). There has been an overall increase in point prevalence in skeletal muscle channelopathies compared to previous reports, with the biggest increase found to be in MC. This can be attributed to next generation sequencing and advances in clinical, electrophysiological and genetic characterisation of skeletal muscle channelopathies.
Assuntos
Síndrome de Andersen , Canalopatias , Paralisia Periódica Hipopotassêmica , Transtornos Miotônicos , Paralisia Periódica Hiperpotassêmica , Humanos , Paralisia Periódica Hiperpotassêmica/genética , Paralisia Periódica Hipopotassêmica/genética , Prevalência , Canalopatias/genética , Sequenciamento de Nucleotídeos em Larga Escala , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Mutação , Músculo Esquelético , Transtornos Miotônicos/genética , Síndrome de Andersen/genéticaRESUMO
Skeletal muscle ion channelopathies are rare genetic diseases mainly characterized by myotonia (muscle stiffness) or periodic paralysis (muscle weakness). Here, we reviewed the available therapeutic options in non-dystrophic myotonias (NDM) and periodic paralyses (PP), which consists essentially in drug repositioning to address stiffness or weakness attacks. Empirical use followed by successful randomized clinical trials eventually led to the orphan drug designation and marketing authorization granting of mexiletine for NDM and dichlorphenamide for PP. Yet, these treatments neither consider the genetic cause of the diseases nor address the individual variability in drug response. Thus, ongoing research aims at the identification of repurposed drugs alternative to mexiletine and dichlorphenamide to allow personalization of treatment. This review highlights how drug repurposing may represent an efficient strategy in rare diseases, allowing reduction of drug development time and costs in a context in which the return on investment may be particularly challenging.
Assuntos
Canalopatias , Transtornos Miotônicos , Paralisias Periódicas Familiares , Humanos , Reposicionamento de Medicamentos , Canalopatias/tratamento farmacológico , Canalopatias/genética , Mexiletina/uso terapêutico , Diclorofenamida/uso terapêutico , Músculo Esquelético , Paralisias Periódicas Familiares/tratamento farmacológico , Paralisias Periódicas Familiares/genética , Transtornos Miotônicos/genética , Transtornos Miotônicos/terapia , MutaçãoRESUMO
PURPOSE OF REVIEW: This article describes the clinical features, diagnosis, pathophysiology, and management of nondystrophic myotonia and periodic paralysis. RECENT FINDINGS: An increasing awareness exists about the genotype-phenotype overlap in skeletal muscle channelopathies, and thus genetic testing is needed to make a definitive diagnosis. Electrodiagnostic testing in channelopathies is highly specialized with significant overlap in various mutation subtypes. Randomized clinical trials have now been conducted in these disorders with expanded treatment options for patients with muscle channelopathies. SUMMARY: Skeletal muscle channelopathies are rare heterogeneous conditions characterized by lifelong symptoms that require a comprehensive management plan that includes pharmacologic and nonpharmacologic interventions. The significant variability in biophysical features of various mutations, coupled with the difficulties of performing clinical trials in rare diseases, makes it challenging to design and implement treatment trials for muscle channelopathies.
Assuntos
Canalopatias , Miotonia , Transtornos Miotônicos , Paralisias Periódicas Familiares , Humanos , Canalopatias/diagnóstico , Canalopatias/genética , Canalopatias/terapia , Músculo Esquelético , Miotonia/diagnóstico , Miotonia/genética , Miotonia/terapia , Transtornos Miotônicos/diagnóstico , Transtornos Miotônicos/genética , Mutação/genéticaRESUMO
The non-dystrophic myotonias are inherited skeletal muscle disorders characterized by skeletal muscle stiffness after voluntary contraction, without muscle atrophy. Based on their clinical features, non-dystrophic myotonias are classified into myotonia congenita, paramyotonia congenita, and sodium channel myotonia. Using whole-exome next-generation sequencing, we identified a L703P mutation (c.2108T>C, p.L703P) in SCN4A in a Chinese family diagnosed with non-dystrophic myotonias. The clinical findings of patients in this family included muscle stiffness and hypertrophy. The biophysical properties of wildtype and mutant channels were investigated using whole-cell patch clamp. L703P causes both gain-of-function and loss-of-function changes in Nav1.4 properties, including decreased current density, impaired recovery, enhanced activation and slow inactivation. Our study demonstrates that L703P is a pathogenic variant for myotonia, and provides additional electrophysiological information for understanding the pathogenic mechanism of SCN4A-associated channelopathies.
Assuntos
Miotonia Congênita , Miotonia , Transtornos Miotônicos , Humanos , Mutação , Miotonia/genética , Miotonia/diagnóstico , Miotonia Congênita/genética , Transtornos Miotônicos/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genéticaRESUMO
INTRODUCTION: Mutations of the skeletal muscle sodium channel gene SCN4A are associated with several neuromuscular disorders including hyper/hypokaliemic periodic paralysis, paramyotonia congenita and sodium channel myotonia. These disorders are distinguished from dystrophic myotonias by the absence of progressive weakness and extramuscular systemic involvement. METHODS: We present an Italian family with 2 subjects carrying a p.Asn1180Ile mutation in SCN4A gene showing a peculiar clinical picture characterized by the association of myopathic features and myotonia. RESULTS: The clinical, electromyographic and histological findings of these patients are reported. The possible pathogenicity of the mutation was tested by three different software, all giving positive results. DISCUSSION: This is the first report of a dominant, heterozygous mutation in SCN4A causing a complex phenotype of non-congenital myopathy and myotonic syndrome. We suggest that, in patients with myotonia and myopathy not related to dystrophic myotonias, the sequence analysis of SCN4A gene should be performed.
Assuntos
Doenças Musculares , Miotonia Congênita , Miotonia , Transtornos Miotônicos , Humanos , Mutação/genética , Miotonia/genética , Miotonia Congênita/genética , Transtornos Miotônicos/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , LinhagemRESUMO
Skeletal muscle sodium channelopathies due to SCN4A gene mutations have a broad clinical spectrum. However, each phenotype has been reported in few cases of Chinese origin. We present detailed phenotype and genotype data from a cohort of 40 cases with SCN4A gene mutations seen in neuromuscular diagnostic service in Huashan hospital, Fudan University. Cases were referred from 6 independent provinces from 2010 to 2018. A questionnaire covering demographics, precipitating factors, episodes of paralysis and myotonia was designed to collect the clinical information. Electrodiagnostic studies and muscle MRI were retrospectively analyzed. The clinical spectrum of patients included: 6 Hyperkalemic periodic paralysis (15%), 18 Hypokalemic periodic paralysis (45%), 7 sodium channel myotonia (17.5%), 4 paramyotonia congenita (10%) and 5 heterozygous asymptomatic mutation carriers (12.5%). Review of clinical information highlights a significant delay to diagnosis (median 15 years), reports of pain and myalgia in the majority of patients, male predominance, circadian rhythm and common precipitating factors. Electrodiagnostic studies revealed subclinical myotonic discharges and a positive long exercise test in asymptomatic carriers. Muscle MRI identified edema and fatty infiltration in gastrocnemius and soleus. A total of 13 reported and 2 novel SCN4A mutations were identified with most variants distributed in the transmembrane helix S4 to S6, with a hotspot mutation p.Arg675Gln accounting for 32.5% (13/40) of the cohort. Our study revealed a higher proportion of periodic paralysis in SCN4A-mutated patients compared with cohorts from England and the Netherlands. It also highlights the importance of electrodiagnostic studies in diagnosis and segregation studies.
Assuntos
Povo Asiático/genética , Canalopatias/genética , Transtornos Miotônicos/genética , Canal de Sódio Disparado por Voltagem NAV1.4 , Paralisias Periódicas Familiares/genética , Adulto , China , Estudos de Coortes , Eletromiografia , Feminino , Genótipo , Humanos , Masculino , Mutação , Miotonia/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Linhagem , Fenótipo , Estudos Retrospectivos , Inquéritos e Questionários , Adulto JovemRESUMO
INTRODUCTION/AIMS: Paramyotonia congenita (PMC) is a skeletal muscle sodium channelopathy characterized by paradoxical myotonia, cold sensitivity, and exercise/cold-induced paralysis. Treatment with sodium-channel-blocking antiarrhythmic agents may expose patients to a risk of arrhythmia or may be poorly tolerated or ineffective. In this study we explored the effectiveness of non-antiarrhythmic sodium-channel blockers in two patients with PMC. METHODS: Earlier treatment with mexiletine was discontinued for gastrointestinal side effects in one of the patients and lack of clinical benefit in the other. One patient received lacosamide, ranolazine, and buprenorphine, and the other was given buprenorphine only. Drug efficacy was assessed by clinical scores, timed tests, and by long and short exercise tests. RESULTS: In both patients, buprenorphine improved pain scores by at least 50%, stiffness and weakness levels, and handgrip/eyelid-opening times. The fall in compound muscle action potential (CMAP) during short exercise normalized in both patients at baseline, and improved after cooling. During long exercise, one patient showed an earlier recovery of CMAP, and the other patient had a less severe decrease (<60%). With buprenorphine, the fall in CMAP induced by cooling normalized in one patient (from -72% to -4%) and improved (from -49% to -37%) in the other patient. DISCUSSION: Buprenorphine showed promising results for the treatment of exercise-induced paralysis and cold intolerance in the two patients assessed. The exercise test may be useful for quantitative assessment of treatment response. Further studies on a larger number of patients, under carefully controlled conditions, should be considered to address the effectiveness and long-term tolerability of this therapeutic option.
Assuntos
Analgésicos Opioides/uso terapêutico , Buprenorfina/uso terapêutico , Transtornos Miotônicos/diagnóstico , Transtornos Miotônicos/tratamento farmacológico , Analgésicos Opioides/farmacologia , Buprenorfina/farmacologia , Teste de Esforço/efeitos dos fármacos , Teste de Esforço/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Miotônicos/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Resultado do TratamentoRESUMO
Skeletal muscle channelopathies are rare genetic neuromuscular conditions that include the nondystrophic myotonias and periodic paralyses. They cause disabling muscle symptoms and can limit educational potential, work opportunities, socialization, and quality of life. Effective therapy is available, making it essential to recognize and treat this group of disorders. Here, the authors highlight important aspects regarding diagnosis and management using illustrative case reports.
Assuntos
Síndrome de Andersen/diagnóstico , Síndrome de Andersen/genética , Canalopatias/diagnóstico , Canalopatias/genética , Paralisia Periódica Hipopotassêmica/diagnóstico , Paralisia Periódica Hipopotassêmica/genética , Adolescente , Síndrome de Andersen/fisiopatologia , Canalopatias/fisiopatologia , Humanos , Paralisia Periódica Hipopotassêmica/fisiopatologia , Masculino , Músculo Esquelético/fisiopatologia , Mutação/genética , Transtornos Miotônicos/diagnóstico , Transtornos Miotônicos/genética , Transtornos Miotônicos/fisiopatologia , Doenças da Junção Neuromuscular/diagnóstico , Doenças da Junção Neuromuscular/genética , Doenças da Junção Neuromuscular/fisiopatologiaRESUMO
Skeletal muscle channelopathies, including non-dystrophic myotonia and periodic paralysis, are rare hereditary disorders caused by mutations of various ion channel genes. To define the frequency of associated mutations of skeletal muscle channelopathies in Japan, clinical and genetic data of two academic institutions, which provides genetic analysis service, were reviewed. Of 105 unrelated pedigrees genetically confirmed, 66 pedigrees were non-dystrophic myotonias [CLCN1 (nâ¯=â¯30) and SCN4A (nâ¯=â¯36)], 11 were hyperkalemic periodic paralysis (SCN4A), and 28 were hypokalemic periodic paralysis [CACNA1S (nâ¯=â¯16) and SCN4A (nâ¯=â¯12)]. Of the 30 families with myotonia congenita, dominant form (Thomsen type) consisted 67%, and unique mutations, A298T, P480T, T539A, and M560T, not found in Western countries, were commonly identified in CLCN1. Hypokalemic periodic paralysis caused by SCN4A mutations consisted 43% in Japan, which was much higher than previous reports. Furthermore, the quality of life of the patients was assessed using the patient-reported outcome measures, SF-36 and INQoL, for 41 patients. This study indicated that the etiology of skeletal muscle channelopathies in Japan was not identical to previous reports from Western countries, and provided crucial information for genetics as well as future therapeutic interventions.
Assuntos
Canalopatias/genética , Músculo Esquelético/patologia , Mutação/genética , Adulto , Canais de Cálcio Tipo L , Feminino , Testes Genéticos , Nível de Saúde , Humanos , Paralisia Periódica Hipopotassêmica/genética , Japão , Masculino , Pessoa de Meia-Idade , Miotonia/genética , Transtornos Miotônicos/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Paralisia Periódica Hiperpotassêmica/genética , Linhagem , Qualidade de Vida , Inquéritos e Questionários , Adulto JovemRESUMO
Non-dystrophic myotonias are a group of rare neuromuscular diseases linked to SCN4A or CLCN1. Among the subtypes, myotonia permanens, associated with the Gly1306Glu variant of SCN4A, is a relatively less frequent but more severe form. Most reports of non-dystrophic myotonias describe European populations. Therefore, to expand the genetic and phenotypic spectrum of this disorder, we evaluated 30 Chilean patients with non-dystrophic myotonias for associated variants and clinical characteristics. SCN4A variants were observed in 28 (93%) of patients, including 25 (83%) with myotonia permanens due to the Gly1306Glu variant. Myotonia permanens was inherited in 24 (96%) patients; the mean age of onset was 6 months, and the initial symptoms were orbicularis oculi myotonia in 17 (74%) patients and larynx myotonia in 12 (52%) patients. The extraocular muscles were involved in 11 (44%) patients, upper limbs in 20 (80%), and lower limbs in 21 (84%). Thirteen (52%) patients experienced recurrent pain and 10 (40%) patients reported limitations in daily life activities. Carbamazepine reduced myotonia in eight treated patients. The high frequency of the Gly1306Glu variant in SCN4A in Chilean patients suggests a founder effect and expands its phenotypic spectrum.
Assuntos
Miotonia/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Adolescente , Adulto , Criança , Chile , Estudos de Coortes , Feminino , Efeito Fundador , Humanos , Lactente , Masculino , Mutação , Transtornos Miotônicos/genética , Adulto JovemRESUMO
Objective: To investigate the clinical, myopathological and genetic mutation characteristics in two Chinese families with paramyotonia congenita (PMC). Methods: Clinical manifestations, electrophysiology, muscle pathology and gene sequencing of two Chinese families with PMC were analyzed retrospectively. Results: Family 1 involved 12 patients in 4 consecutive generations and family 2 involved only 1 patient in 3 generations. The onset of symptoms in all patients started at early childhood. Both probands presented with myotonia triggered by cold and paroxysmal weakness. However, the other 11 patients in family 1 only manifested cold-induced myotonia. Serum creatine kinase (CK) was slightly elevated between attacks of weakness in the 2 probands, and was even greater than 10 000 U/L during the episodes of weakness in the second proband, whose lower limb MRI revealed edema in bilateral medial gastrocnemius. Electromyography showed diffuse myotonia discharge and myogenic impairment in both probands, and myotonia discharge in the first proband's mother. Muscle pathology of both probands showed mild myopathic changes, and tube aggregation was occasionally observed in the second one. Genetic testing revealed a maternally inherited heterozygous R1448H mutation of SCN4A gene in the first proband and part of his family. A novel heterozygous R1448G mutation of SCN4A gene was reported in the second proband. Conclusions: Cold-triggered myotonia with or without paroxysmal weakness are the common characteristics of PMC. Myotonic potential and myogenic impairment can be tested in electromyography. The p.R1448G mutation is a new missense mutation.
Assuntos
Miotonia Congênita , Transtornos Miotônicos , Criança , Pré-Escolar , Humanos , Mutação , Mutação de Sentido Incorreto , Miotonia Congênita/genética , Transtornos Miotônicos/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Linhagem , Estudos RetrospectivosAssuntos
Transtornos Miotônicos/diagnóstico , Transtornos Miotônicos/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Criança , Diagnóstico Diferencial , Humanos , Masculino , Contração Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Transtornos Miotônicos/fisiopatologiaAssuntos
Rigidez Muscular/etiologia , Mutação de Sentido Incorreto , Miotonia/etiologia , Transtornos Miotônicos/diagnóstico , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Criança , Temperatura Baixa/efeitos adversos , Diagnóstico Diferencial , Teste de Esforço , Feminino , Força da Mão , Humanos , Rigidez Muscular/genética , Miotonia/diagnóstico , Miotonia/genética , Transtornos Miotônicos/genética , Distrofia Miotônica/diagnóstico , Canal de Sódio Disparado por Voltagem NAV1.4/deficiência , Osteocondrodisplasias/diagnóstico , Recidiva , Distúrbios da Fala/etiologiaRESUMO
The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.
Assuntos
Fadiga/fisiopatologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/fisiopatologia , Mialgia/fisiopatologia , Transtornos Miotônicos/fisiopatologia , Acetazolamida/uso terapêutico , Idade de Início , Inibidores da Anidrase Carbônica/uso terapêutico , Canais de Cloreto/genética , Eletrodiagnóstico , Eletromiografia , Testes Genéticos , Humanos , Lamotrigina/uso terapêutico , Mexiletina/uso terapêutico , Miotonia Congênita/tratamento farmacológico , Miotonia Congênita/genética , Miotonia Congênita/fisiopatologia , Transtornos Miotônicos/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Guias de Prática Clínica como Assunto , Ranolazina/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêuticoRESUMO
INTRODUCTION: Mutations of the voltage-gated sodium channel gene (SCN4A), which encodes Nav1.4, cause nondystrophic myotonia that occasionally is associated with severe apnea and laryngospasm. There are case reports of nondystrophic myotonia due to mutations in the C-terminal tail (CTerm) of Nav1.4, but the functional analysis is scarce. METHODS: We present two families with nondystrophic myotonia harboring a novel heterozygous mutation (E1702del) and a known heterozygous mutation (E1702K). RESULTS: The proband with E1702K exhibited repeated rhabdomyolysis, and the daughter showed laryngospasm and cyanosis. Functional analysis of the two mutations as well as another known heterozygous mutation (T1700_E1703del), all located on EF hand-like motif in CTerm, was conducted with whole-cell recording of heterologously expressed channel. All mutations displayed impaired fast inactivation. DISCUSSION: The CTerm of Nav1.4 is vital for regulating fast inactivation. The study highlights the importance of accumulating pathological mutations of Nav1.4 and their functional analysis data.
Assuntos
Motivos EF Hand/genética , Potenciais da Membrana/fisiologia , Mutação/genética , Transtornos Miotônicos/diagnóstico , Transtornos Miotônicos/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Pré-Escolar , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Miotônicos/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Paramyotonia congenita (PC; OMIM 168300) is a non-dystrophic myotonia caused by mutations in the SCN4A gene. Transient muscle stiffness, usually induced by exposure to cold and aggravated by exercise, is the predominant clinical symptom, and interictal persistent weakness is uncommon. CASE REPORT: We report a family with a history of PC accompanied by persistent hand muscle weakness with masticatory muscle involvement. Persistent weakness was exacerbated with age, and MR analysis showed marked atrophy of temporal, masseter, and finger flexor muscles with fatty replacement. The PC causative mutation T1313M in the SCN4A gene was prevalent in the family. Administration of acetazolamide chloride improved clinical symptoms and the results of cold and short exercise tests. Phenotypic variation within the family was remarkable, as the two younger affected patients did not present with persistent weakness or muscle atrophy. CONCLUSIONS: PC associated with the T1313M mutation is a possible cause of persistent distal hand weakness.
Assuntos
Debilidade Muscular , Músculo Esquelético , Transtornos Miotônicos , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Músculos Faciais/diagnóstico por imagem , Músculos Faciais/patologia , Músculos Faciais/fisiopatologia , Mãos/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Músculos da Mastigação/diagnóstico por imagem , Músculos da Mastigação/patologia , Músculos da Mastigação/fisiopatologia , Debilidade Muscular/etiologia , Debilidade Muscular/genética , Debilidade Muscular/patologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Transtornos Miotônicos/complicações , Transtornos Miotônicos/genética , Transtornos Miotônicos/patologia , Transtornos Miotônicos/fisiopatologia , LinhagemRESUMO
Nondystrophic myotonias are disorders of Na+ (Nav1.4 or SCN4A) and Cl- (CLCN1) channels in skeletal muscles, and frequently show phenotype heterogeneity. The molecular mechanism underlying their pathophysiology and phenotype heterogeneity remains unclear. As zebrafish models have been recently exploited for studies of the pathophysiology and phenotype heterogeneity of various human genetic diseases, a zebrafish model may be useful for delineating nondystrophic myotonias. Here, we generated transgenic zebrafish expressing a human mutant allele of SCN4A, referred to as Tg(mylpfa:N440K), and needle electromyography revealed increased number of myotonic discharges and positive sharp waves in the muscles of Tg(mylpfa:N440K) than in controls. In addition, forced exercise test at a water temperature of 24⯰C showed a decrease in the distance moved, time spent in and number of visits to the zone with stronger swimming resistance. Finally, a forced exercise test at a water temperature of 18⯰C exhibited a higher number of dive-bombing periods and drifting-down behavior than in controls. These findings indicate that Tg(mylpfa:N440K) is a good vertebrate model of exercise- and cold-induced human nondystrophic myotonias. This zebrafish model may contribute to provide insight into the pathophysiology of myotonia in sodium channelopathy and could be used to explore a new therapeutic avenue.